Neurodegenerative disorders and Drugs for ALS

  1. Neurodegenerative disorders
    general principles
    • -Diffuse; but not always symmetric (Parkinsonism, ALS)
    • -Chronic (progressive) over many years; onset is typically insidious... occurs after long period of normal nervous system function. Latent period, degeneration is occuring without symptoms
    • -Irreversible degeneration
    • -No treatments that slow or reverse the progression of the disease
    • -Little cellular response or tissue reaction (gliosis)
    • -CSF is typically normal
    • -leads to cell death (apoptosis, aggregations of nl or abnormal proteins) and loss of tissue, which can lead to atrophy
    • -...
    • -Some are from unstable nucleotide repeats
    • -Threshold that leads to an impairment of gene function and the clinical disorder
    • -anticipation (earlier onset in affected offspring)
    • -Potentiation (worsening of disease in affected offspring
    • -coding region repeat (Huntington's disease) tend to have neurodegenerative disorder that starts midlife; polyglutamine expansion leads to toxic gain of function
    • -Noncoding regions (myotonic dystrophy and fragile X syndrome) result in decreased protein synthesis and a loss of function; typically involve multiple systems
    • -...
    • -Hereditary degenerative polyneuropathies
    • onset and progression varry
  2. Alzheimer's disease
    presentation, epidemiology
    Gradually worsening dementia over years, with preservation of sensory and motor function

    Onset: insidious, slow progression

    • Presentation: Most pts begin with the basic amnesia syndrome which can progress to anomia, impairment of visuospatial skills, and executive dysfunction.
    • -Neuropsychiatric features include depression, delusions, hallucinations
    • -Mortality is most often due to medical illness (average is 8.5 years post onset of forgetfullness)
    • -Common disorder; atypical presentations are often seen

    • Epidemiology: Age is the only major risk factor
    • -1% of 65 year olds; Incidence doubles every 5 years thereafter!
    • -32% of 90 year olds have Alzheimer's

    • *Risk factor within age groups:
    • Apolipoprotein E genotype modifies the likelihood of older individual developing Alzheimer's
    • -more ε4 alleles increase a persons risk; ε2 is protective
    • -Head trauma, female sex, low education
    • -All pts with Down's syndrome will develop Alzheimer's during 40s-50s

    There is atosomal dominant Alzheimer's (early onset); but less than 1% of pts wtih Alzheimer's have this form
  3. Alzheimer's
    • Pathology: required for dx: shows gross atrophy that is most severe in the cerebral higher cortex (especially medial temporal lobe structures important for memory)
    • -Microscopic: neuronal loss, gliosis, abnormal neuritic plaques and neurofibrillary tangles

    • 1. Cerebral atrophy: narrowing of gyri, enlargement of sulci
    • -"hydrocephalus" ex vacuo

    2. Neuronal loss and gliosis are present

    • 3. Neuritic plaques: focal, spherical collections of dystrophic neuritic processes often surrounding a central core of amyloid
    • -Proteins of amyloid core are Aβ40 and Aβ42
    • - Plaques seen first in the association neocortex and later are found in the hippocampus
    • Image Upload 2

    • 4. Neurofibrillary tangles: bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus. "flame shaped", easy to see in silver stain
    • -Tangles are seen first in the entorhinal cortex, then in the hippocampus, then in the temporal and other neocortex; amygdala, basal forebrain, median raphe nuclei
    • -tangles contain paired helical filaments
    • -abnormally hyperphosphorylated forms of the protein tau
    • -Filaments also contain the microtubule associated protein MAP2 and ubiquitin

    Tangles are not specific for Alzheimer's disease
  4. Alzheimer's
    • Pathophysiology: deposition of Aβ peptides that result from the abnormal processing of the amyloid precursor protein (APP)
    • -APP has an unknown function

    Image Upload 4

    inflammatory response to the aggregates of amyloid. may contribute to the abnormal tau phosphorylation and oxidative injury to neurons
  5. Alzheimer's
    evaluation and treatment
    • Evaluation: Dx is made on history and exam
    • -neuroimaging may not show atrophy
    • -some lab tests may be ordered to r/o other conditions
    • -No good biomarkers

    • Treatment:
    • Non-pharmacologic therapy remains the mainstay of therapy
    • -education, continue activity for as long as possible, outpatient care for as long as possible, stop driving

    • Pharmacologic therapy: not very effective
    • -Cholinesterase inhibitors - efficacy is equal
    • 1. Donepezil - also approved for severe Alzheimer's (not just mild-moderate...)
    • 2. Galantamine
    • 3. Rivastigmine (patch available)

    AEs: nausea, diarrhea

    -Memantine  - low affinity NMDA receptor antagonist (approved for moderate to severe Alzheimer's disease)
  6. Fronto-temporal lobar degenerations
    Heterogeneous group of neurodegenerative disorders

    Onset: 40s-50s (younger than those with Alzheimer's); chronic, progressive abnormalities of "frontal lobe syndrome"

    -Some progressive behavioral disorder, or progressive aphasia

    • Pick's disease: well defined form of fronto-temporal lobar degeneration
    • -typically asymmetrical cortical atrophy in the frontal and anterior portions of the temporal lobe

    Image Upload 6
  7. Parkinson's disease
    idiopathic Parkinson's disease 

    Presentation, epidemiology, pathology
    Gradually worsening motor dysfunction, often with additional autonomic, cognitive neuropsychiatric or additional abnormalities

    • Presentation:
    • 1. Onset: 45 to 70 years (peak in the 60s)

    2. Motor dysfunction (asymmetric) that includes hyper- (tremor) and hypokinetic (bradykinesia, akinesia, rigidity, postural instability and decreased associated movements)

    • 3. Initial symptoms:
    • -Tremor 70%
    • -Gait disturbance 11%
    • -Stiffness 10%
    • -Slowness 10%
    • -Muscle aches 8%
    • ...
    • -Depression, nervousness, other psych disturbances 4%

    4. Autonomic dysfunction: constipation, seborrhea, excessive sweating, orthostatic hypotension

    5. Cognitive and neuropsychiatric dysfunction and depression. Dementia may be present in ~15% of patients, but increases with age

    6. REM sleep behavior disorder may occur before the motor manifestations

    7. Variable course - most have significant motor disability within 10 years

    • Epidemiology:
    • -1% of 65 year olds; 3% of 85 year olds (not exponential like Alzheimer's)
    • -Whites > Asians, blacks
    • -Familial Parkinson's disease is rare
    • -Almost always sporadic
    • -Environmental risk factors: pesticides
    • -Nicotine and caffeine may offer a very small degree of protection

    • Pathology:
    • -Pallor of the substantia nigra and of the locus ceruleus (locus ceruleus is in the ponto-midbrain junction; NE projection system)
    • -Surviving pigmented neurons may contain  Lewy bodies (eosinophilic core with clear halo)
    • alpha-synuclein

    Image Upload 8

    *mediam raphe (5-HT projection system) also affected)
  8. Parkinson's disease

    Pathophysiology, evaluation, and treatment
    • Pathophysiology:
    • 1. Loss of dopaminergic projections ..."too few movements"
    • -Depression in Parkinson's disease is most likely due to degeneration of the locus ceruleus (source of noradrenergic projections) and median raphe (source of serotonergic projections).

    2. Decrease in # of cells in substantia nigra; 30% or less of aged matched controls

    • 3. α-synuclein appears to play a role in the neural degeneration in Parkinson's disease; major component of Lewy bodies
    • -normal component of the synapse... instability or misfolding may lead to PD

    4. Pt treated with graft of fetal substantia nigra... 10 years later, the graft will have Parkinson's disease 

    • Evaluation: Dx is based on history and exam
    • -asymmetric
    • -good response to DA replacement
    • -no labs to support the dx; no biomarkers

    • Therapy:
    • -management of various features (orthostatic hypotension, neurogenic bladder, constipation, drooling)
    • -Delerium is typically transient
    • -Depression is treated in the usual manner
    • -REM sleep behavior disorders are treated with  meds that suppress REM sleep

    • Non-pharmacologic therapy:
    • -various therapy (occupational, physical...)
    • -Deep brain stimulation: adjustable, reversible, 'destructive' lesion of the subthalamic nucleus
    •       - Just as effective as Rx, but can be set at continual level (Rx tend to fluctuate in efficacy based on dose, which cycles up and down)

    • Pharmacologic therapy: Purely symptomatic
    • -Carbidopa/levodopa +/- COMT inhibitor (entacapone)
    • -Dopamine agonist (ropinirole)
    • -Muscarinic acetylcholine receptor antagonists (trihexyphenidyl, particularly effective for tremor)
    • -amantadine (NMDA glutamate receptor antagonist ... might not be mechanism of action in treating PD)
    • -monoamine oxidase B inhibitors (selegiline)

    *as disease progresses, pt becomes less responsive to drugs; drugs more likely to be used in combination
  9. Dementia with Lewy bodies
    Clinical overlap with both Alzheimer's and Parkinson's disease; pathologically is more similar to Parkinson's disease

    • Pathology: Lewy bodies in the cortex (diffuse)
    • -less distinct (not as eosinophilic); lack the halo
    • -contain predominantly α-synuclein

    Pathophysiology: unknown

    • Presentation:
    • -Parkinsonism, dementia, fluctuations in alertness and attention, and hallucination within the same year.
    • -Second most common form of progressive dementia seen in elderly
    • -Death on average 8 years post onset of symptoms
    • -Tx is difficult: pts are prone to have hallucinations... balance DA therapy (too much leads to hallucination, too little leads to parkinsonism)
  10. Huntington's disease
    Prototypical polyglutamine trinucleotide repeat expansion disorder

    • Autosomal dominant gene codes for protein huntingtin. Threshold is 35 repeats
    • -more repeats: earlier onset
    • -Paternal transmission is associated with anticipation and potentiation.
    • -function of normal gene is not known
    • -Gain of toxic function... selective regions are vulnerable to this toxicity (caudate> putamen)

    • Pathology: 
    • -Atrophy of caudate more than the putamen (apparent grossly and on neuroimaging)
    • -nucleus accumbens (third part of the striatum) is preserved
    • -loss of neurons, particularly of the medium spiny neurons, which give rise to direct and indirect pathways of the basal ganglia circuit
    • -protein aggregates containing huntingtin are found on surviving neurons

    • Clinical: 4-5 per million
    • -Autosomal dominant, complete penetrance
    • -Age of onset is 30s to 40s
    • -gradually worsening loss of sccadic eye movements, chorea, frontal syndrome and other neuropsychiatric dysfunction that may include depression and suicide
    • -clinical onset to death, ~15 years
    • -earlier onset can present with hypokinetic movement disorder > chorea

    • Tx: symptomatic and supportive
    • -DA depeleters (tetrabenazine) to suppress choria
  11. Amyotrophic lateral sclerosis (ALS)
    Lou Gehrig's disease

    • Clinical: gradual progressive asymmetrical lower and upper motor neuron dysfunction in an older patient
    • -Asymmetrical atrophy and weakness of the hands is a common presentation
    • -50% die in 3 years
    • -90% die within 6 years

    • Epidemiology: ~1 per 100,000
    • -Men > women  (2:1)
    • -onset is normally >45 years, incidence increases with age
    • -Most is sporadic; 5 to 10% have familial form of ALS

    • Pathology
    • -Anterior roots of the spinal cord and precentral gyrus appears atrophic (motor)
    • Image Upload 10

    • -microscopically, reduction in # of anterior horn cells. reactive gliosis
    • -surviving motor neurons often contain PAS-positive cytoplasmic inclusions called Bunina bodies
    • -stained sections of cord show loss of myelinated axons in the lateral cortical spinal tract.
    • -Muscles show neurogenic atrophy

    • Pathophysiology: not known for the sporadic ALS
    • -several genes identified in the familial ALS; most with autosomal dominant trait: copper-zinc superoxide dismutase (SOD1)

    • Evaluation: Clinical; based on history and exam
    • -EMG can confirm suspicion of widespread LMN dysfunction, though not found early in course
    • -MRI, labs to rule out other causes...

    • Tx: symptomatic and supportive
    • -antimuscarinics for drooling
    • -baclofen (GABA B agonist) for spasticity
    • -dextromethorphan for Pseudobulbar affect (inappropriate response to social situation)
    • -dietary fiber, fluids for constipation
    • -Ventilator
    • -Feeding tubes

    • -Riluzole: only FDA approved drug that slows the course of ALS; extends trach-free survival by 2 to 3 months...
    • -mechanism not known; AEs include nausea,,, abdominal discomfort, hepatotoxicity
  12. Spinal Muscular Atrophy
    • Clinical: autosomal recessive
    • -onset is infantile: birth, or within months
    • -One in every 20,000 live births: 2nd most frequent cause of death from an autosomal recessive disorder
    • -babies become weak and "floppy"; LMN disorder worsens and child typically dies before the age of one year

    • Cause:
    • -homozygous mutations of the survival motor neuron 1 (SMN1) gene.
    • -Clinical severity is inversely related to the number of copies of SMN2, highly homologous nearby gene. Lots of SMN2 means less severe disease and later onset
    • -SMN protein may be important for axonal transport, but appears to promote survival of motor neurons

    • Pathology: loss of the anterior horn cells and brain stem motor neuron nerve cell bodies
    • -associated reactive gliosis
    • -Motor roots atrophy
    • -Muscle pathology: atrophic fibers and scattered abnormally large muscle fibers

    • Image Upload 12
  13. Charcot Marie Tooth "disorder"
    Group of hereditary motor and sensory degenerative polyneuropathies

    • CMT type 1:
    • -Autosomal dominant inheritance 
    • -demyelinating

    • CMT1A (letter indicates mutation subtype)
    • -duplication of region that codes for Peripheral myelin protein 22 (PMP22) which is expressed in compact myelin and is involved in the myelin compaction process in the PNS.

    • Pathology: peripheral nerves show repetitive demyelination and remyelination with multiple onion bulbs that are most prominent distally
    • -segmental demyelination can be seen

    • Clinical: 1 in 2,500 individuals have CMT, majority is CMT1
    • -Sx start by age 30, but progression is slow
    • -symmetrical, predominantly motor, distal polyneuropathy
    • -lower extremity atrophy ("stork leg" appearance) and weakness, very high arched feet, and "hammer toes"
    • -Peripheral nerves may be enlarged to palpation (onion bulb process)
    • -Can be mild; many people with CMT never come to medical attention

    -Pts live normal lifespan, treatment is supportive, dx is based on history, PE, and genetic testing to confirm
  14. Myotonic dystrophy
    • Pathophysiology: Abnormal CTG trinucleotide repeat expansion on chromosome 19 that affects the mRNA for the "dystrophia myotonia protein kinase"
    • -Most common muscular dystrophy in adults

    • Normal people have <30 repeats; severe myotonic dystrophy pts can have thousands of repeats
    • -Anticipation occurs
    • -repeat expansion is in a non-coding region results in decreased protein synthesis and loss of function

    • Clinical: multisystem disorder affecting 13.5 per 100,000 live births
    • -Autosomal dominant with variable (but high) penetrance
    • -Onset: any age, most often in young adults
    • -progressive weakness and myotonia that often affects levator palpebrae, muscles of mastication and facial expression, sternocleidomastoid muscle
    • *characteristic appearance

    • -weakness is often distal
    • -Myotonia - delayed relaxation of a muscle following vigorous contraction

    -frontal baldness, cataracts, gonadal atrophy, cardiomyopathy, abnormal glucose tolerance, sleep apnea, lower IQ

    Tx: supportive, genetic counseling

    • Pathology: Skeletal muscle shows variation in fiber size, and may have internal nuclei
    • -Ring fiber - a subsarcolemmal band of cytoplasm that appears distinct from the center of the fiber
  15. Duchenne's muscular dystrophy
    • Pathophysiology: loss of the protein dystrophin due to many different mutations
    • -Dystrophin is one of the largest genes; high rate of mutation
    • -Most mutations are deletions, the rest are frameshift or point
    • -Cytoplasmic protein that is located adjacent to the cell membrane of the muscle: it forms (with an associated complex) a link between the contractile apparatus within the muscle cell and the connective tissue of the ECM
    • -role in transferring force of muscle contraction to surrounding tissue
    • -loss of this protein leads to degeneration of the muscle

    • Pathology:  variation in muscle fiber size, increased number of internal nuclei; degeneration, necrosis, phagocytosis of muscle fibers
    • -regeneration also apparent (but not enough to keep up with the degeneration)
    • -proliferation of endomysial connective tissue
    • -muscle is replaced by fat and connective tissue

    • Clinical: most common form of muscular dystrophy; 1 per 3,500 live male births
    • -2/3rds are X-linked recessive, males affected, females asymptomatic carriers
    • -1/3 are new mutations
    • -onset: <3 years; always by age of 6 years
    • -symmetrical and proximal > distal weakness; progressive
    • -Pseudohypertrophy of calf muscle (initial hypertrophy of muscle, subsequently replaced with fat)
    • -death occurs between adolescence and mid-20s

    • Evaluation/Tx: Dx is suspected by history and exam
    • -CK is markedly elevated
    • -Genetic testing confirms, though not all can be detected
    • -muscle bx reveals an absence of dystrophin
    • -Tx: supportive, genetic counseling
    • -Glucocorticoids may delay progression of weakness (keep them walking), but significant adverse effects
  16. Drugs for ALS
    • Disease specific therapy: Riluzole
    • Spasticity: Baclofen (GABAreceptor agonist) and Tizanidine (α2 receptor agonist)
    • SKM spasms, cramps: Carbamazepine, Phenytoin
    • Sialorrhea: Atropine, Botulinum toxin
    • Pseudobulbar affect: Dextromethorphan + quinidine
Card Set
Neurodegenerative disorders and Drugs for ALS
Degenerative neuro, ALS drugs